Genetic Variant NM_000523.4:c.174_182dupGGCGGCGGC (chr2-176093057-G-GGGCGGCGGC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_000523.4(HOXD13):c.174_182dupGGCGGCGGC(p.Ala59_Ala61dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,369,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

HOXD13
NM_000523.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.191

Publications

1 publications found

Variant links:

Genes affected

HOXD13 (HGNC:5136): (homeobox D13) This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXD genes located in a cluster on chromosome 2. Deletions that remove the entire HOXD gene cluster or the 5' end of this cluster have been associated with severe limb and genital abnormalities. Mutations in this particular gene cause synpolydactyly. [provided by RefSeq, Jul 2008]

HOXD13 Gene-Disease associations (from GenCC):

brachydactyly-syndactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
synpolydactyly type 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
brachydactyly type E
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 5
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HOXD13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000523.4

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOXD13	NM_000523.4 link	c.174_182dupGGCGGCGGC	p.Ala59_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2	ENST00000392539.4	NP_000514.2	P35453
HOXD13	XM_011511068.3 link	c.725-1416_725-1408dupGGCGGCGGC		intron_variant	Intron 1 of 1		XP_011509370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOXD13	ENST00000392539.4 link	c.174_182dupGGCGGCGGC	p.Ala59_Ala61dup	disruptive_inframe_insertion	Exon 1 of 2	1	NM_000523.4	ENSP00000376322.3		P35453

Frequencies

GnomAD3 genomes

AF:

0.0000730

AC:

AN:

150788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000279

AC:

AN:

1219016

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

595806

show subpopulations

African (AFR)

AF:

0.0000416

AC:

AN:

24022

American (AMR)

AF:

0.00

AC:

AN:

10562

Ashkenazi Jewish (ASJ)

AF:

0.000706

AC:

AN:

16992

East Asian (EAS)

AF:

0.00

AC:

AN:

28024

South Asian (SAS)

AF:

0.0000199

AC:

AN:

50160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4814

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

1003622

Other (OTH)

AF:

0.000100

AC:

AN:

50020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000795

AC:

AN:

150896

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73668

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41364

American (AMR)

AF:

0.000132

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

67440

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over